Penetration enhancers for transdermal delivery of systemic agents

ABSTRACT

This invention relates to a method for administering systemically active agents including therapeutic agents through the skin or mucosal membranes of humans and animals in a transdermal device or formulation comprising topically administering with said systemic agent an effective amount of a membrane penetration enhancer having the structural formula ##STR1## wherein X may represent sulfur, oxygen or nitrogen; a and b may be 0 or 1, c may be 0, 1 or 2, except that when X is oxygen, a, b and c are 0, when X is nitrogen c is 0 and only one of a or b is 1, and when X is sulfur a and b are 0; A is a branched or a straight chain, divalent aliphatic radical having from 0 to 2 double bonds; R&#39; is selected from the group consisting of H, a lower alkyl group having from 1 to 4 carbon atoms, phenyl, lower alkyl or halogen substituted phenyl, acetamido, halogen, piperidinyl, lower alkyl or halogen substituted piperidinyl, carboalkoxy, carboxamide, and alkanoyl; and R is hydrogen or a lower alkyl group having from 1 to 4 carbon atoms, ##STR2## wherein R&#34; is H or halogen, and salts, e.g. acid or quaternary derivatives, thereof. These compositions are useful in topical or transdermal applications of the physiologically-active agent.

REFERENCE TO EARLIER FILED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 897,043,entitled COMPOSITIONS COMPRISING 1-OXOHYDROCARBYL-SUBSTITUTEDAZACYCLOHEXANES, filed on Aug. 15, 1986 abandoned.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The invention generally relates to an improved method of drug delivery.More particularly, the invention relates to an improved membranepenetration enhancer for use in the transdermal delivery of systemicallyactive drugs to humans and animals.

(2) Background of the Prior Art

For some years, pharmaceutical researchers have sought an effectivemeans of introducing drugs into the bloodstream by applying them tounbroken skin. Among other advantages, such administration can provide acomfortable, convenient, and safe way of giving many drugs now takenorally or infused into veins or injected intramusculalry. Using skin asthe portal for drug entry offers unique potential, because transdermaldelivery permits close control over drug absorption. For example, itavoids factors that can cause unpredictable absorption from thegastrointestinal tract, including: changes in acidity, motility, andfood content. It also avoids initial metabolism of the drug by theliver. Thus, controlled drug entry through skin can achieve a highdegree of control over blood concentrations of drug.

Close control over drug concentrations in blood can translate readilyinto safer and more comfortable treatment. When a drug's adverse effectsoccur at higher concentrations than its beneficial ones, rate controlcan maintain the concentrations that evoke only--or principally thedrug's desired actions. This ability to lessen undesired drug actionscan greatly reduce the toxicity hazards that now restrict or prevent theuse of many valuable agents.

Transdermal delivery particularly benefits patients with chronicdisease. Many such patients have difficulty following regimens requiringseveral doses daily of medications that repeatedly cause unpleasantsymptoms. They find the same drugs much more acceptable whenadministered in transdermal systems that require applicationinfrequently--in some cases, only once or twice weekly--and that reduceadverse effects.

Transdermal delivery is feasible for drugs effective in amounts that canpass through the skin area and that are substantially free of localizedirritating or allergic effects. While these limitations may exclude someagents, many others remain eligible for transdermal delivery. Moreover,their numbers will expand as pharmaceutical agents of greater potencyare developed. Particularly suitable for transdermal delivery are potentdrugs with only a narrow spread between their toxic and safe bloodconcentrations, those having gastrointestinal absorption problems, orthose requiring frequent dosing in oral or injectable form.

Transdermal therapy permits much wider use of natural substances such ashormones. Often the survival times of these substances in the body areso short that they would have to be taken many times daily in ordinarydosage forms. Continuous transdermal delivery provides a practical wayof giving them, and one that can mimic the body's own patterns ofsecretion.

At present, controlled transdermal therapy appears feasible for manydrugs used for a wide variety of ailments including, but not limited to,circulatory problems, hormone deficiency, respiratory ailments, and painrelief.

Percutaneous administration can have the advantage of permittingcontinuous administration of drug to the circulation over a prolongedperiod of time to obtain a uniform delivery rate and blood level ofdrug. Commencement and termination of drug therapy are initiated by theapplication and removal of the dosing devices from the skin.Uncertainties of administration through the gastrointestinal tract andthe inconvenience of administration by injection are eliminated. Since ahigh concentration of drug never enters the body, problems of pulseentry are overcome and metabolic half-life is not a factor ofcontrolling importance.

U.S. Pat. Nos. 3,989,815; 3,989,816; 3,991,203; 4,122,170; 4,316,893;4,415,563; 4,423,040; 4,424,210; and 4,444,762 generally describe amethod for enhancing the topical (as contrasted to the systemic)administration of physiologically active agents by combining such anagent with an effective amount of a penetration enhancer and applyingthe combination topically to humans or animals, in the form of creams,lotions, gels, etc.

Penetration enhancers for enhancing systemic administration oftherapeutic agents transdermally are cited in U.S. Pat. Nos. 4,405,616;4,562,075; 4,031,894, 3,996,934; and 3,921,636.

SUMMARY OF THE INVENTION

It has been discovered that the penetration enhancers previouslydisclosed in U.S. patent application Ser. No. 897,043 to enhance topicaldelivery of physiologically active agents also enhance the transdermaldelivery of systemically active agents through the skin or other bodymembranes of humans and animals directly into the bloodstream.

The invention therefore provides a method for topically administeringsystemically active agents through the skin or mucosal membranes ofhumans and animals, utilizing a transdermal device or formulation,wherein the improvement in said method comprises topically administeringwith said systemic agent an effective amount of a membrane penetrationenhancer having the structural formula ##STR3## wherein X may representsulfur, oxygen or nitrogen; a and b may be 0 or 1, c may be 0, 1 or 2,except that when X is oxygen, a, b and c are 0, when X is nitrogen c is0 and only one of a or b is 1, and when X is sulfur a and b are 0; A isa branched or a straight chain, divalent aliphatic radical having from 0to 2 double bonds; R' is selected from the group consisting of H, alower alkyl group having from 1 to 4 carbon atoms, phenyl, acetamido,halogen, piperidinyl, lower alkyl or halogen substituted piperindinyl,carbalkoxy, carboxamide, and alkanoyl; and R is hydrogen or a loweralkyl group having from 1 to 4 carbon atoms, ##STR4## wherein R" is H orhalogen, and salts, e.g. quaternary salts thereof.

The invention also provides an improved method for administeringsystemically active therapeutic agents topically through the skin ofhumans in a transdermal device or formulation to obtain therapeuticblood levels of the therapeutic agent, wherein the improvement in saidmethod comprises the use of an effective skin penetration enhancingamount of the above membrane penetration enhancer, with said therapeuticagent.

Preferably, R is hydrogen or a lower alkyl group, e.g. methyl, R' is H,X is oxygen and A is a divalent radical represened by the generalformula

    --CH.sub.2 --.sub.n

wherein n is 0 to 17.

In a more preferred embodiment of the present invention, n is 4-16, e.g.10.

DETAILED DESCRIPTION OF THE INVENTION

The compounds useful as membrane penetration-enhancers in theformulations or devices of the instant invention may be made asdescribed in U.S. patent application Ser. No. 897,043 herebyincorporated by reference.

These 1-oxohydrocarbyl-substituted derivatives of morpholine,thiomorpholine and piperazine, useful in the present invention includecompounds represented by the general formulae: ##STR5## wherein R, R'and A are as defined above.

The compounds are also useful in the present invention as acid andquaternary derivatives. In particular, compounds represented by formulaII are conveniently converted into salts, e.g. acid and quaternaryderivatives represented by the general formula: ##STR6## In thecompounds represented by formula VII, R is preferably hydrogen or alower alkyl group group, e.g. a methyl radical group.

Topical examples of compounds represented by the above structuralformula include:

4-(1-oxododecyl)morpholine

2,6-dimethyl-4-(1-oxohexadecyl)morpholine

2,6-dimethyl-4-(1-oxooctadecyl)morpholine

2,6-dimethyl-4-(1-oxododecyl)morpholine

2,6-dimethyl-4-(1-oxotridecyl)morpholine

2,6-dimethyl-4-(1-oxotetradecyl)morpholine

2,6-dimethyl-4-(1-oxoundecyl)morpholine

4-(1-oxooctadecyl)morpholine

4-(1-oxononyl)morpholine

4-(1-oxodecyl)morpholine

4-(1-oxododecyl)morpholine

4-(1-oxohexadecyl)morpholine

4-(1-oxotetradecyl)morpholine

4-(1-oxooctyl)morpholine

4-(1-oxohexyl)morpholine

4-(1-oxoheptyl)morpholine

4-(1-oxopentyl)morpholine

4-(1-oxoundec-1-enyl)morpholine

4-(1-oxodeca-1,3-dienyl)morpholine

4-(1-oxononadecyl)morpholine

4-(1-oxundecyl)morpholine

4-(1-oxoheptadecyl)morpholine

4-(1-oxopentadecyl)morpholine

4-(1-oxo-16-methylheptadecyl)morpholine

2,6-dimethyl-4-(1-oxodecyl)morpholine

4-(1-oxotridecyl)morpholine

4,4'-(1-dioxo-1,6-hexanediyl)bismorpholine

1-(1-oxohexadecyl)piperazine

1-(1-oxoheptadecyl)piperazine

1-(1-oxopentyl)piperazine

1,1'-(1,9-dioxo-1,9-nonanediyl)bis-piperazine

1,1'-(1,10-dioxo-1,10-decanediyl)bis-piperazine

4,4'-(1,6-dioxo-1,6-hexanediyl)bis-thiomorpholine

1,1'-(1,10-dioxo-1,10-decanediyl)bis[4-methylpiperazine]

1,1'-(1,6-dioxo-1,6-hexanediyl)bis[4-methylpiperazine]

1,1'-(1,7-dioxo-1,7-heptanediyl)bis[4-methylpiperazine]

1,4-bis(1-oxodecyl)-piperazine

1-methyl-4-(1-oxodecyl)-piperazine

1,4-bis(1-oxododecyl)-piperazine

1-methyl-4-(1-oxohexyl)-piperazine

1,4-bis(1-oxohexyl)-piperazine

1,4-bis(1-oxoheptyl)-piperazine

1,4-bis(1-oxooctyl)-piperazine

1-(1-oxododecyl)-4-methyl-piperazine

1,4-bis(16-methyl-1-oxoheptadecyl)-piperazine

1,4-bis(1-oxohexadecyl)-piperazine

1,4-bis(1-oxoctadecyl)-piperazine

1-methyl-4-(1-oxohexadecyl)-piperazine

1-methyl-4-(1-oxooctadecyl)-piperazine

1-methyl-4-(1-oxoheptyl)-piperazine

1-methyl-4-(1-oxooctyl)-piperazine

1-methyl-4-(1-oxonoyl)-piperazine

1-methyl-4-(1-oxotetradecyl)-piperazine

1-methyl-4-(1-oxoundecyl)-piperazine

1,1-methyl-4-(1-oxoundecyl)-piperazine

4-(1-oxododecyl)piperazinium chloride

Typical systemically active agents which may be delivered transdermallyare therapeutic agents which are sufficiently potent such that they canbe delivered through the skin or other membrane to the bloodstream insufficient quantities to produce the desired therapeutic effect. Ingeneral, this includes therapeutic agents in all of the majortherapeutic area including, but not limited to, anti-infectives, such asantibiotics and antiviral agents, analgesics and analgesic combinations,anorexics, anthelmintics, antiarthritics, antiasthma agents,anticonvulsants, antidepressants, antidiabetic agents, antidiarrheals,antihistamines, anti-inflammatory agents, antimigraine preparations,antimotion sickness, antinauseants, antineoplastics, antiparkinsonismdrugs, antipruritics, antipsychotics, antipyretics, antispasmodics,including gastrointestinal and urinary; anticholinergics,sympathomimetics, xanthine derivatives, cardiovascular preparationsincluding calcium channel blockers, beta-blockers, antiarrhythmics,antihypertensives, diuretics, vasodilators including general, coronary,peripheral and cerebral; central nervous system stimulants, cough andcold preparations, decogestants, diagnostics, hormones, hypnotics,immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetics, psychostimulants, sedatives and tranquilizers.

Dosage forms for application to the skin or other membranes of humansand animals include creams, lotions, gels, ointments, suppositories,sprays, aerosols, buccal and sub-lingual tablets and any one of avariety of transdermal devices for use in the continuous administrationof systemically active drugs by absorption through the skin, oral mucosaor other membranes, see, for example, one or more of U.S. Pat. Nos.3,598,122; 3,598,123; 3,731,683; 3,742,951; 3,814,097; 3,921,636;3,972,995; 3,993,072; 3,993,073, 3,996,934; 4,031,894; 4,060,084;4,069,307; 4,201,211; 4,230,105; 4,292,299 and 4,292,303. U.S. Pat. No.4,077,407 and the foregoing patents also disclose a variety of specificsystemically active agents which may also be useful in transdermaldelivery, which disclosures are hereby incorporated herein by thisreference.

Typical inert carriers which may be included in the foregoing dosageforms include conventional formulating materials, such as, for example,water, isopropyl alcohol, gaseous fluorocarbons, ethyl alcohol,polyvinyl pyrrolidone, propylene glycol, fragrances, gel-producingmaterials such as "Carbopol", stearyl alcohol, stearic acid, spermaceti,sorbitan monooleate, "Polysorbates", "Tweens", sorbital,methylcellulose, etc.

Systemically active agents are used in amounts calculated to achieve andmaintain therapeutic blood levels in a human or animal over the periodof time desired. These amounts vary with the potency of eachsystemically active substance, the amount required for the desiredtherapeutic or other effect, the rate of elimination or breakdown of thesubstance by the body once it has entered the bloodstream and the amountof penetration-enhancer in the formulation. In accordance withconventional prudent formulating practices, a dosage near the lower endof the useful range of a particular agent is usually employed initiallyand the dosage increased or decreased as indicated from the observedresponse, as in the routine procedure of the physician.

The amount of penetration enhancer which may be used in the inventionvaries from about 1 to 100 percent although adequate enhancement ofpenetration is generally found to occur in the range of about 1 to about10 percent by weight of the formulation to be delivered. Thepenetration-enhancer disclosed herein may be used in combination withthe active agent or may be used separately as a pre-treatment of theskin or other body membrane through which the systemically-active agentis intended to be delivered.

The invention is further illustrated by the following examples which areillustrative of a specific mode of practicing the invention and is notintended as limiting the scope of the appended claims.

EXAMPLE 1

A composition, in the form of a gel, suitable for transdermal deliveryof haloperidol, an antidyskinetic or antipsychotic drug, is prepared bymixing the following components in the given concentrations.

    ______________________________________                                        Component              Weight %                                               ______________________________________                                        Haloperidol            1-5                                                    N-(1-Oxodecyl)morpholine                                                                             1-10                                                   Carbopol 934 P         0.5-2                                                  (Available from                                                               B. F. Goodrich)                                                               Neutralizing Agent     q.s.                                                   (NaOH)                                                                        Tween-20               1-10                                                   (Available from                                                               Atlas Chemical, a                                                             Div. of I.C.I.)                                                               Preservative           q.s.                                                   (Sorbic Acid)                                                                 Antioxidant            q.s.                                                   (Ascorbic Acid)                                                               Chelating Agent        q.s.                                                   (Disodium salt of                                                             ethylenediaminetetraacetic                                                    acid)                                                                         Deionized Water        q.s. to 100                                            ______________________________________                                    

This composition is topically applied to the skin of a human subject andafter the passage of a suitable period of time haloperidol is found inthe bloodstream of said subject.

EXAMPLE 2

When an amine, e.g. triethylamine or triethanolamine, is substituted forNaOH the results are substantially similar, i.e. a topical compositionsuitable for transdermally delivering haloperidol to the bloodstream isobtained.

EXAMPLE 3

When potassium sorbate, or a lower alkyl paraben, e.g. methyl, ethyl,propyl or butyl paraben are substituted for the preservative of thecomposition of Example 1, the results are substantially similar, i.e. atopical composition suitable for the transdermal delivery of haloperidolto the bloodstream is obtained.

EXAMPLE 4

When ascorbyl palmitate, Vitamin E, thioglycerol, thioglycolic acid,sodium formaldehyde sulfoxylate, BHA, BHT, propyl gallate or sodiummetabisulfite are substituted for the antioxidant of the compositionformulated in Example 1, the results are substantially similar in that atopical composition suitable for transdermally delivering haloperidol tothe bloodstream is obtained.

EXAMPLE 5

The composition of Example 1 is prepared in the form of a sodiumalginate gel by mixing the following components in the following givenconcentrations:

    ______________________________________                                        Component              Weight %                                               ______________________________________                                        Haloperidol            1-5                                                    N-(1-oxodecyl)morpholine                                                                             1-10                                                   Sodium Alginate        0.5-5                                                  Calcium Salts          q.s.                                                   Tween-20               1-10                                                   Preservative*          q.s.                                                   Antioxidant**          q.s.                                                   Chelating Agent***     q.s.                                                   Deionized Water        to 100                                                 ______________________________________                                         *Suitable preservatives are those used in Example 3 as well as sorbic         acid.                                                                         **Suitable antioxidants are those used in Example 4 including ascorbic        acid.                                                                         ***The chelating agent is the disodium salt of ethylenediaminetetraacetic     acid.                                                                    

This composition when applied topically is found to transdermallydeliver haloperidol to the bloodstream of a subject.

EXAMPLE 6

The composition of Example 1 is prepared in the form of a hydrophiliccream by mixing the following components.

    ______________________________________                                        Component              Weight %                                               ______________________________________                                        Oil Phase                                                                     Cetyl Alcohol          5-15                                                   Stearyl Alcohol        1-5                                                    N-(1-Oxodecyl)morpholine                                                                             0.5-10                                                 Glycerol Monostearate  2-7                                                    Water Phase                                                                   Sodium Laurylsulfate   0.1                                                    Solvent*               2-20                                                   Tween-20               1-5                                                    Water                  q.s. to 100                                            ______________________________________                                         *Suitable solvents are propylene glycol, glycerin, alcohols, for example,     ethyl alcohol, isopropyl alcohol, etc. and polyethylene glycols.         

The oil phase and the water phase is made up separately, and thenagitated to form an emulsion. (When, as in Example 8, the activeingredient, is other than haloperidol, depending on its lipophilicity,it will be distributed in the oil or water phase.) This hydrophiliccream, when applied topically to the skin of a human, is found totransdermally delivery haloperidol into the bloodstream.

EXAMPLE 7

The composition of the instant invention may also be delivered by use ofa polymeric matrix. For example, a solid polymer such as cellulosetriacetate, polyvinyl acetate, terpolymers and copolymers of vinylchloride and vinyl acetate, copolymers of polyvinyl alcohol andpolyvinyl acetate, and silicon elastomers is imbibed with a liquidhaving the following components in the given concentrations.

    ______________________________________                                        Component              Weight %                                               ______________________________________                                        Polymer                5-40                                                   Haloperidol            q.s.                                                   N-(1-Oxodecyl)morpholine                                                                             0.5-80                                                 Solvent*               5-90                                                   Surfactant**           1-10                                                   Preservative***        q.s.                                                   Antioxidant****        q.s.                                                   ______________________________________                                         *Solvents may be the solvents used in Example 6 above.                        **The Surfactant may be Tween20, glycerol monostearate or sodium              laurylsulfate, etc.                                                           ***The preservative may be any of the preservatives used in Example 3         above.                                                                        ****The antioxidants may be any of those used in Example 4 above.        

When solid matrix, containing the active ingredients formulated above,is contacted with the skin of a human subject, after a period of timethe active agent is found in the bloodstream of said subject.

EXAMPLE 8

Examples 1 to 7 are repeated except that the following activeingredients in the given concentrations are substituted for haloperidol:

    ______________________________________                                        Active Ingredient     Weight %                                                ______________________________________                                        Isosorbide Dinitrate  5-15                                                    Nitroglycerin         1-5                                                     Estradiol             1-5                                                     Clonidine             0.5-3                                                   Propranolol           1-5                                                     Indomethacine         5-15                                                    Nifedipine            1-5                                                     Nicardipine           1-5                                                     Diclorofenac          5-15                                                    Metaproterenol        1-5                                                     ______________________________________                                    

Similar results are obtained in that the active ingredient istransdermally delivered to the bloodstream of an animal.

EXAMPLE 9

Examples 1 to 8 are repeated except that the compounds exemplified onpage 7 (except for N-(1-oxodecyl)-morpholine) are substituted forN-(1-oxodecyl)morpholine. Similar results are obtained in that theactive ingredients are transdermally delivered to the bloodstream of ananimal.

In particular, N-(1-oxodecyl)-piperazine,1,4-bis(1-oxodecyl)-piperazine,1,1-dihydrogen-4-(1-oxodecyl)piperazinium chloride andN-(1-oxodecyl)thiomorpholine are effective penetration-enhancers for themethods and devices of the present invention.

While particular embodiments of the invention have been described itwill be understood of course that the invention is not limited theretosince many obvious modifications can be made and it is intended toinclude within this invention any such modifications as will fall withinthe scope of the appended claims.

Having now described the invention, we claim:
 1. A method for enhancingpenetration of systemically active agents through the skin or mucosalmembranes and into the bloodstream of humans and animals, said methodcomprising the topical administration of effective amounts of asystemically active agent and of a membrane penetration enhancer havingthe structural formula ##STR7## wherein X may represent sulfur, oxygenor nitrogen; a and b may be 0 or 1, c may be 0, 1 or 2, except that whenX is oxygen, a, b and c are 0, when X is nitrogen c is 0 and only one ofa or b is 1, and when X is sulfur a and b are 0; A is a branched or astraight chain, divalent aliphatic radical having from 0 to 2 doublebonds; R' is selected from the group consisting of H, a lower alkylgroup having from 1 to 4 carbon atoms, phenyl, lower alkyl or halogensubstituted phenyl, acetamido, halogen, piperidinyl, lower alkyl orhalogen substituted piperidinyl, carbalkoxy, carboxamide, and alkanoyl;and R is hydrogen or a lower alkyl group having from 1 to 4 carbonatoms, ##STR8## wherein R" is H or halogen, and salts thereof.
 2. Themethod of claim 1 wherein R is hydrogen or a lower alkyl group, R' is H,X is oxygen, and A is a divalent radical represented by the generalformula --(CH₂)_(n) wherein n is 0 to
 17. 3. The method of claim 2wherein n is 4 to
 16. 4. The method of claim 3 wherein n is
 10. 5. Themethod of claim 1 wherein the systemically active agent is therapeuticagent.
 6. The method of claim 5 wherein the administration isconcurrent.
 7. The method of claim 1 wherein the membrane penetrationenhancer is selected from the group consisting ofN-(1-oxodecyl)morpholine, N-(1-oxodecyl)-piperazine,1,4-bis(1-oxodecyl)piperazinium chloride andN-(1-oxodecyl)thiomorpholine.
 8. The method of claim 1 wherein thesystemically active agent is selected from the group consisting ofhaloperidol, isosorbide dinitrate, nitroglycerin, estradiol, clonidine,propranolol, indomethacin, nifedipine, nicardipine, diclorofenac andmetaproterenol.
 9. The method of claim 7 wherein the systemically activeagent is selected from the group consisting of haloperidol, isosorbidedinitrate, nitroglycerin, estradiol, clonidine, propranolol,indomethacin, nifedipine, nicardipine, diclorofenac and metaproterenol.